BLOOD BIOMARKERS FOR SUICIDALITY
Biomarkers and methods for screening expression levels of the biomarkers for predicting and tracking suicidality, as well as for monitoring response to a treatment for suicidal risk and for determining suicidal risk as a side-effect of an antidepressant are disclosed.
1 . A method for identifying a subject at risk for suicide, the method comprising:
obtaining a reference expression level of a blood biomarker; and
determining an expression level of the blood biomarker in a sample obtained from the subject, wherein a change in the expression level of the blood biomarker in the sample obtained from the subject as compared to the reference expression level indicates a risk for suicide.
2 . The method of claim 1 , wherein the expression level of the blood biomarker in the sample obtained from the subject is increased as compared to the reference expression level of the biomarker.
3 . The method of claim 2 , wherein the blood biomarker is selected from the group consisting of spermidine/spermine N1-acetyltransferase 1 (SAT1); forkhead box N3 (FOXN3); guanylate binding protein 1 (GBP1); phosphoinositide-3-kinase regulatory subunit 5 (PIK3R5); apolipoprotein L2 (APOL2); ATPase H+ transporting lysosomal 9 kDa, V0 subunit e1 (ATP6V06E1); GRINL1A complex locus (GCOM1); interleukin 1 beta (IL1B); lipoma HMGIC fusion partner (LHFP); lipase A (LIPA); myristoylated alanine-rich protein kinase C substrate (MARCKS); 6-phosphogluconolactonase (PGLS); phosphatase and tensin homolog (PTEN); reversion-inducing-cysteine-rich protein with kazal motifs (RECK); tumor necrosis factor (ligand) superfamily member 10 (TNFSF10); ATP-binding cassette, subfamily A (ABC1) member 1 (ABCA1); Rho guanine nucleotide exchange factor (GEF) 40 (ARHGEF4; FLJ10357); cancer susceptibility candidate 1 (CASC1); dehydrogenase/reductase (SDR family) member 9 (DHRS9); disrupted in schizophrenia 1 (DISC1); eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2); uncharacterized LOC727820 (LOC727820); mitogen-activated protein kinase kinase kinase 3 (MAP3K3); mitochondrially encoded NADH dehydrogenase 6 (MT-ND6; ND6); RNA binding motif protein 47 (RBM47); RPTOR independent companion of MTOR complex 2 (RICTOR); sterile alpha motif domain containing 9-like (SAMD9L); scavenger receptor class F member 1 (SCARF1); solute carrier family 36 (proton/amino acid symporter) member 1 (SLC36A1); signal transducer and activator of transcription 1, 91 kDa (STAT1); cytochrome c oxidase subunit Vb (COX5B); SWI/SNF related matrix associated actin dependent regulator of chromatin subfamily a member 1 (SMARCA1); ubiquitin-like modifier activating enzyme 6 (UBA6); zinc finger CCCH-type antiviral 1 (ZC3HAV1); tyrosine kinase, non-receptor 2 (TNK2), and combinations thereof.
4 . The method of claim 1 , wherein the expression level of the blood biomarker in the sample obtained from the subject is decreased as compared to the reference expression level of the biomarker.
5 . The method of claim 4 , wherein the blood biomarker is selected from the group consisting of cluster 4 antigen (CD24; CD24 molecule); ATPase type 13A2 (ATP13A2); epoxide hydrolase 1, microsomal (xenobiotic) (EPHX1); HtrA serine peptidase 1 (HTRA1); leptin receptor (LEPR); spectrin beta non-erythrocytic 1 (SPTBN1); muscleblind-like 2 (MBNL2); olfactory receptor family 2 subfamily J member 3 (OR2J3); Ras homolog enriched in brain (RHEB); glutamate receptor, ionotropic, N-methyl D-aspartate-associated protein 1 (GRINA); D-box binding protein, promyelocytic leukemia (PML), potassium inwardly-rectifying channel, subfamily J, member 2 (KCNJ2), topoisomerase (DNA) 1 (TOP 1) and combinations thereof.
6 . The method of claim 1 , wherein the change in expression level is about 1.2 fold or greater as compared to the reference expression level.
7 . The method of claim 1 , wherein the sample obtained from the subject is blood.
8 . The method of claim 1 , wherein the expression of the blood biomarker is selected from the group consisting of spermidine/spermine N1-acetyltransferase 1 (SAT1); forkhead box N3 (FOXN3); guanylate binding protein 1 (GBP1); phosphoinositide-3-kinase regulatory subunit 5 (PIK3R5); apolipoprotein L2 (APOL2); ATPase H+ transporting lysosomal 9 kDa, V0 subunit e1 (ATP6V06E1); GRINL1A complex locus (GCOM1); interleukin 1 beta (IL1B); lipoma HMGIC fusion partner (LHFP); lipase A (LIPA); myristoylated alanine-rich protein kinase C substrate (MARCKS); 6-phosphogluconolactonase (PGLS); phosphatase and tensin homolog (PTEN); reversion-inducing-cysteine-rich protein with kazal motifs (RECK); tumor necrosis factor (ligand) superfamily member 10 (TNFSF10); ATP-binding cassette, subfamily A (ABC1) member 1 (ABCA1); Rho guanine nucleotide exchange factor (GEF) 40 (ARHGEF4; FLJ10357); cancer susceptibility candidate 1 (CASC1); dehydrogenase/reductase (SDR family) member 9 (DHRS9); disrupted in schizophrenia 1 (DISC1); eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2); uncharacterized LOC727820 (LOC727820); mitogen-activated protein kinase kinase kinase 3 (MAP3K3); mitochondrially encoded NADH dehydrogenase 6 (MT-ND6; ND6); RNA binding motif protein 47 (RBM47); RPTOR independent companion of MTOR complex 2 (RICTOR); sterile alpha motif domain containing 9-like (SAMD9L); scavenger receptor class F member 1 (SCARF1); solute carrier family 36 (proton/amino acid symporter) member 1 (SLC36A1); signal transducer and activator of transcription 1, 91 kDa (STAT1); cytochrome c oxidase subunit Vb (COX5B); SWI/SNF related matrix associated actin dependent regulator of chromatin subfamily a member 1 (SMARCA1); ubiquitin-like modifier activating enzyme 6 (UBA6); zinc finger CCCH-type antiviral 1 (ZC3HAV1); tyrosine kinase, non-receptor 2 (TNK2), and combinations thereof in the blood sample of the subject is increased as compared to the reference expression level, and wherein the expression of the blood biomarker selected from the group consisting of cluster 4 antigen (CD24; CD24 molecule); ATPase type 13A2 (ATP13A2); epoxide hydrolase 1, microsomal (xenobiotic) (EPHX1); HtrA serine peptidase 1 (HTRA1); leptin receptor (LEPR); spectrin beta non-erythrocytic 1 (SPTBN1); muscleblind-like 2 (MBNL2); olfactory receptor family 2 subfamily J member 3 (OR2J3); Ras homolog enriched in brain (RHEB); glutamate receptor, ionotropic, N-methyl D-aspartate-associated protein 1 (GRINA); D-box binding protein, promyelocytic leukemia (PML), potassium inwardly-rectifying channel, subfamily J, member 2 (KCNJ2), topoisomerase (DNA) 1 (TOP1) and combinations thereof in the blood sample of the subject is decreased as compared to the reference expression level.
9 . A method for monitoring response of a subject to a treatment for suicidal risk, the method comprising:
obtaining an expression level of a biomarker from the subject;
administering a treatment for suicidal risk to the subject; and
determining an expression level of the biomarker in a sample obtained from the subject after the treatment is administered, wherein a change in the expression level of the biomarker in the sample obtained from the subject after the treatment is administered as compared to the expression level of the biomarker before the treatment is administered indicates a response to the treatment.
10 . The method of claim 9 , wherein the response is an increase in expression level of the biomarker.
11 . The method of claim 10 , wherein the biomarker is selected from the group consisting of small cell lung carcinoma cluster 4 antigen (CD24; CD24 molecule); ATPase type 13A2 (ATP13A2); epoxide hydrolase 1, microsomal (xenobiotic) (EPHX1); HtrA serine peptidase 1 (HTRA1); leptin receptor (LEPR); spectrin beta non-erythrocytic 1 (SPTBN1); muscleblind-like 2 (MBNL2); olfactory receptor family 2 subfamily J member 3 (OR2J3); Ras homolog enriched in brain (RHEB); glutamate receptor, ionotropic, N-methyl D-aspartate-associated protein 1 (GRINA); D-box binding protein, promyelocytic leukemia (PML), potassium inwardly-rectifying channel, subfamily J, member 2 (KCNJ2), topoisomerase (DNA) 1 (TOP1) and combinations thereof.
12 . The method of claim 9 , wherein the response is a decrease in expression level of the biomarker.
13 . The method of claim 12 , wherein the biomarker is selected from the group consisting of spermidine/spermine N1-acetyltransferase 1 (SAT1); forkhead box N3 (FOXN3); guanylate binding protein 1 (GBP1); phosphoinositide-3-kinase regulatory subunit 5 (PIK3R5); apolipoprotein L2 (APOL2); ATPase H+ transporting lysosomal 9 kDa, V0 subunit e1 (ATP6V06E1); GRINL1A complex locus (GCOM1); interleukin 1 beta (IL1B); lipoma HMGIC fusion partner (LHFP); lipase A (LIPA); myristoylated alanine-rich protein kinase C substrate (MARCKS); 6-phosphogluconolactonase (PGLS); phosphatase and tensin homolog (PTEN); reversion-inducing-cysteine-rich protein with kazal motifs (RECK); tumor necrosis factor (ligand) superfamily member 10 (TNFSF10); ATP-binding cassette, subfamily A (ABC1) member 1 (ABCA1); Rho guanine nucleotide exchange factor (GEF) 40 (ARHGEF4; FLJ10357); cancer susceptibility candidate 1 (CASC1); dehydrogenase/reductase (SDR family) member 9 (DHRS9); disrupted in schizophrenia 1 (DISC1); eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2); uncharacterized LOC727820 (LOC727820); mitogen-activated protein kinase kinase kinase 3 (MAP3K3); mitochondrially encoded NADH dehydrogenase 6 (MT-ND6; ND6); RNA binding motif protein 47 (RBM47); RPTOR independent companion of MTOR complex 2 (RICTOR); sterile alpha motif domain containing 9-like (SAMD9L); scavenger receptor class F member 1 (SCARF1); solute carrier family 36 (proton/amino acid symporter) member 1 (SLC36A1); signal transducer and activator of transcription 1, 91 kDa (STAT1); cytochrome c oxidase subunit Vb (COX5B); SWI/SNF related matrix associated actin dependent regulator of chromatin subfamily a member 1 (SMARCA1); ubiquitin-like modifier activating enzyme 6 (UBA6); zinc finger CCCH-type antiviral 1 (ZC3HAV1); tyrosine kinase, non-receptor 2 (TNK2), and combinations thereof.
14 . The method of claim 9 , wherein the treatment for suicidal risk is selected from the group consisting of a drug, a nutritional, and combinations thereof.
15 . The method of claim 14 , wherein the drug is selected from the group consisting of clozapine, lithium, IL-1 trap, canakinumab, nicorandil, amiodarone, arsenic trioxide, vemurafenib, elsamitrucin, T 0128, CT-2106, BN80927, tafluposide, TAS-103, beta-lapachone, irinotecan, top( ) tecan, 9-amino-20-camptothecin, rubitecan, gimatecan, karenitecin, and combinations thereof.
16 . The method of claim 14 , wherein the nutritional is an omega-3 fatty acid.
17 . The method of claim 9 , wherein the sample obtained from the subject is selected from the group consisting of whole blood, leukocytes, megakaryocytes, brain, cerebrospinal fluid, olfactory epithelium cells, fibroblasts from skin biopsies, induced pluripotent stem cells, and neuronal-like cells derived therefrom.
18 . The method of claim 9 , wherein the biomarker is selected from the group consisting of spermidine/spermine N1-acetyltransferase 1 (SAT1); forkhead box N3 (FOXN3); guanylate binding protein 1 (GBP1); phosphoinositide-3-kinase regulatory subunit 5 (PIK3R5); apolipoprotein L2 (APOL2); ATPase H+ transporting lysosomal 9 kDa, V0 subunit e1 (ATP6V06E1); GRINL1A complex locus (GCOM1); interleukin 1 beta (IL1B); lipoma HMGIC fusion partner (LHFP); lipase A (LIPA); myristoylated alanine-rich protein kinase C substrate (MARCKS); 6-phosphogluconolactonase (PGLS); phosphatase and tensin homolog (PTEN); reversion-inducing-cysteine-rich protein with kazal motifs (RECK); tumor necrosis factor (ligand) superfamily member 10 (TNFSF10); ATP-binding cassette, subfamily A (ABC1) member 1 (ABCA1); Rho guanine nucleotide exchange factor (GEF) 40 (ARHGEF4; FLJ10357); cancer susceptibility candidate 1 (CASC1); dehydrogenase/reductase (SDR family) member 9 (DHRS9); disrupted in schizophrenia 1 (DISC1); eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2); uncharacterized LOC727820 (LOC727820); mitogen-activated protein kinase kinase kinase 3 (MAP3K3); mitochondrially encoded NADH dehydrogenase 6 (MT-ND6; ND6); RNA binding motif protein 47 (RBM47); RPTOR independent companion of MTOR complex 2 (RICTOR); sterile alpha motif domain containing 9-like (SAMD9L); scavenger receptor class F member 1 (SCARF1); solute carrier family 36 (proton/amino acid symporter) member 1 (SLC36A1); signal transducer and activator of transcription 1, 91 kDa (STAT1); cytochrome c oxidase subunit Vb (COX5B); SWI/SNF related matrix associated actin dependent regulator of chromatin subfamily a member 1 (SMARCA1); ubiquitin-like modifier activating enzyme 6 (UBA6); zinc finger CCCH-type antiviral 1 (ZC3HAV1); tyrosine kinase, non-receptor 2 (TNK2), and combinations thereof in the blood sample of the subject is increased as compared to the reference expression level, and wherein the expression of the blood biomarker selected from the group consisting of cluster 4 antigen (CD24; CD24 molecule); ATPase type 13A2 (ATP13A2); epoxide hydrolase 1, microsomal (xenobiotic) (EPHX1); HtrA serine peptidase 1 (HTRA1); leptin receptor (LEPR); spectrin beta non-erythrocytic 1 (SPTBN1); muscleblind-like 2 (MBNL2); olfactory receptor family 2 subfamily J member 3 (OR2J3); Ras homolog enriched in brain (RHEB); glutamate receptor, ionotropic, N-methyl D-aspartate-associated protein 1 (GRINA); D-box binding protein, promyelocytic leukemia (PML), potassium inwardly-rectifying channel, subfamily J, member 2 (KCNJ2), topoisomerase (DNA) 1 (TOP1) and combinations thereof in the blood sample of the subject is decreased as compared to the reference expression level.
19 . A method for determining suicidal risk as a side-effect of an antidepressant, the method comprising:
obtaining an expression level of a biomarker from a subject;
administering an antidepressant to the subject; and
determining an expression level of the biomarker in a sample obtained from the subject after the antidepressant is administered, wherein a change in the expression level of the biomarker in the sample obtained from the subject after the antidepressant is administered as compared to the expression level of the biomarker before the antidepressant is administered indicates suicidal risk as a side-effect of the antidepressant.
20 . The method of claim 19 , wherein the antidepressant is selected from the group consisting of bupropion, citalopram, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, and venlafaxine.
21 . The method of claim 19 , wherein the biomarker is selected from the group consisting of spermidine/spermine N1-acetyltransferase 1 (SAT1); forkhead box N3 (FOXN3); guanylate binding protein 1 (GBP1); phosphoinositide-3-kinase regulatory subunit 5 (PIK3R5); apolipoprotein L2 (APOL2); ATPase H+ transporting lysosomal 9 kDa, V0 subunit e1 (ATP6V06E1); GRINL1A complex locus (GCOM1); interleukin 1 beta (IL1B); lipoma HMGIC fusion partner (LHFP); lipase A (LIPA); myristoylated alanine-rich protein kinase C substrate (MARCKS); 6-phosphogluconolactonase (PGLS); phosphatase and tensin homolog (PTEN); reversion-inducing-cysteine-rich protein with kazal motifs (RECK); tumor necrosis factor (ligand) superfamily member 10 (TNFSF10); ATP-binding cassette, subfamily A (ABC1) member 1 (ABCA1); Rho guanine nucleotide exchange factor (GEF) 40 (ARHGEF4; FLJ10357); cancer susceptibility candidate 1 (CASC1); dehydrogenase/reductase (SDR family) member 9 (DHRS9); disrupted in schizophrenia 1 (DISC1); eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2); uncharacterized LOC727820 (LOC727820); mitogen-activated protein kinase kinase kinase 3 (MAP3K3); mitochondrially encoded NADH dehydrogenase 6 (MT-ND6; ND6); RNA binding motif protein 47 (RBM47); RPTOR independent companion of MTOR complex 2 (RICTOR); sterile alpha motif domain containing 9-like (SAMD9L); scavenger receptor class F member 1 (SCARF1); solute carrier family 36 (proton/amino acid symporter) member 1 (SLC36A1); signal transducer and activator of transcription 1, 91 kDa (STAT1); cytochrome c oxidase subunit Vb (COX5B); SWI/SNF related matrix associated actin dependent regulator of chromatin subfamily a member 1 (SMARCA1); ubiquitin-like modifier activating enzyme 6 (UBA6); zinc finger CCCH-type antiviral 1 (ZC3HAV1); tyrosine kinase, non-receptor 2 (TNK2); cluster 4 antigen (CD24; CD24 molecule); ATPase type 13A2 (ATP13A2); epoxide hydrolase 1, microsomal (xenobiotic) (EPHX1); HtrA serine peptidase 1 (HTRA1); leptin receptor (LEPR); spectrin beta non-erythrocytic 1 (SPTBN1); muscleblind-like 2 (MBNL2); olfactory receptor family 2 subfamily J member 3 (OR2J3); Ras homolog enriched in brain (RHEB); glutamate receptor, ionotropic, N-methyl D-aspartate-associated protein 1 (GRINA); D-box binding protein, promyelocytic leukemia (PML), potassium inwardly-rectifying channel, subfamily J, member 2 (KCNJ2), topoisomerase (DNA) 1 (TOP 1) and combinations thereof.